Bridging the gap: axonal fusion drives rapid functional recovery of the nervous system

Abstract

Injuries to the central or peripheral nervous system frequently cause long-term disabilities because damaged neurons are unable to efficiently self-repair. This inherent deficiency necessitates the need for new treatment options aimed at restoring lost function to patients. Compared to humans, a number of species possess far greater regenerative capabilities, and can therefore provide important insights into how our own nervous systems can be repaired. In particular, several invertebrate species have been shown to rapidly initiate regeneration post-injury, allowing separated axon segments to re-join. This process, known as axonal fusion, represents a highly efficient repair mechanism as a regrowing axon needs to only bridge the site of damage and fuse with its separated counterpart in order to re-establish its original structure. Our recent findings in the nematode Caenorhabditis elegans have expanded the promise of axonal fusion by demonstrating that it can restore complete function to damaged neurons. Moreover, we revealed the importance of injury-induced changes in the composition of the axonal membrane for mediating axonal fusion, and discovered that the level of axonal fusion can be enhanced by promoting a neuron's intrinsic growth potential. A complete understanding of the molecular mechanisms controlling axonal fusion may permit similar approaches to be applied in a clinical setting.

Flagging fusion: Phosphatidylserine signaling in cell–cell fusion

“…Cell repair elicited by PM insults also employs exofacial PS. Exposure of PS on injured axons initiates axonal fusion, a highly efficient mechanism of nervous system repair (reviewed, ( 152 , 153 )). This finding is especially interesting because this fusion process involves the C. elegans fusogen EFF-1, and to the best of our knowledge, this is the only indication in the literature suggesting that fusions mediated by “Fusion Family” (FF) proteins (including C. elegans EFF-1 and AFF-1 and gamete-expressed HAP2) may, as all other fusion processes discussed above, depend on PS exposure.…”

Administration of CoCl2 Improves Functional Recovery in a Rat Model of Sciatic Nerve Transection Injury

“…Peripheral nerve regeneration is a complex process involving restoring the interrupted neuronal connectivity and resulting in functional recovery 34 . Treatments for nerve transection injury have addressed a variety of scientific disciplines, including reconstructive microsurgery, transplantation, biomaterial science, physical therapy, and genetic pharmacotherapy 35 - 37 . Previous studies have demonstrated that hypoxic stress may induce the expression of multiple genes and affect functional recovery of axon regeneration through HIF pathway 11 , 13 , 14 , 38 , 39 .…”

Closing the Gap Between Mammalian and Invertebrate Peripheral Nerve Injury: Protocol for a Novel Nerve Repair

“…In certain invertebrate species, WD does not occur for weeks to months after an axon is severed. The regenerating axons frequently make contact with intact distal segment axons and auto-fuse, which restores axon continuity between proximal and distal segments and enables recovery of nerve function within days [ 4 - 6 ]. Auto-fusion occurs with high specificity, as existing evidence suggests that regenerating axons can recognize and fuse with their original distal ends.…”

“…Additionally, invertebrates such as C elegans do not have injury-induced immune responses that are present in mammals [ 6 ]. Overall, the immune response to PNI in mammals is conducive to successful nerve regeneration [ 3 ].…”

“…Numerous interventions have demonstrated the ability to delay WD in mammals when implemented prior to nerve injury or within a 4- to 6-hour critical window after the time of injury [ 16 ]. These interventions include cryotherapy and the administration of ascorbic acid (vitamin C) [ 6 , 7 , 16 - 19 ].…”